Cancer is defined as any of various malignant neoplasia characterized by the proliferation of anaplastic cells. The cancer cells invade the surrounding tissue and metastasize to new sites in the body. Every year, nearly one million new cancer cases are being detected annually in this country. Cancer is the second most common cause of death in the U.S. followed by cardiovascular disease. Cancer accounts for one in every four deaths. The American Cancer Society predicts that in 2017, there would be an estimated 1,688,780 new cancer cases diagnosed and 600,920 cancer deaths in the US. Genetic factors, tobacco, alcohol consumption, foods contaminated with aflatoxins, dietary and behavioral aspects, and chemicals are the main factors that increase cancer risk.
Traditional cancer treatment mainly involves the use of chemotherapy and radiation therapy. There are several side effects of chemotherapy and radiation therapy. The following are various side effects of chemotherapy and radiation therapy: immunosuppression, infections, fatigue, exhaustion (physical, emotional, or mental exhaustion), pain, mouth and throat sores, diarrhea, nausea and vomiting, constipation blood disorders, nervous system weakness, death of healthy cells causing weakness, and anemia.
There is ample evidence for natural formulations being taken into the main stream for the prevention and treatment of the cancer patients, infections, and pain/inflammation. As there are less or no side effects from compositions derived from natural entities, such as plants and arthropods that are members of Arachnids class and order Scorpiones based compounds.
Plants are the mainstay of medicine and credited with mystical and almost supernatural of powers of healing. The ultimate objective of their use is that they should interact directly with physiological chemistry. In recent times the trend of researching new natural or herbal compositions has increased. Further identifying new medicines for the treatment of cancer from natural products is preferred, as the compositions and medications with natural formulations have less or no side effects.
In global platform, herbs have been in use for treating diseases. In modern practice of cancer chemotherapy, several plants derived formulations are routinely used as potent cytotoxic agents. There is immense opportunity for exploring and finding anticancer treatments and natural formulations across veterinary and human application.
The world has seen the use of very promising anti-cancer agents like Taxol, Topotecan, and Periwinkle. The medical literature in India and the traditional system of medicines and classical records provide details of the etiopathogenesis and management of tumors and cancerous conditions. In nature, scorpion chlorotoxins immobilize the envenomated prey. Research has shown that chlorotoxins bind preferentially. It has been shown that certain chlorotoxins will preferentially bind to glioma cells, compared with non-neoplastic cells or normal brain, allowing development of new methods for the treatment and diagnosis of several types of cancer. (J Neurooncol. 2005 May; 73(1):1-7, Scorpion venom induces glioma cell apoptosis in vivo and inhibits glioma tumor growth in vitro. By Wang W X1, Ji Y H.). Notably, scorpions provide a vast opportunity for discovering new chlorotoxins. Scorpions are part of the order Scorpiones and the class Arachnida. They are invertebrates that possess eight legs, and a two-segmented body composed of the cephalothorax and the abdomen. This is the classification of scorpions: Kingdom Animalia (Animals); Phylum: Arthropoda (Arthropods); Subphylum: Chelicerata; Class: Arachnida (Arachnids); and Order: Scorpiones (Scorpions). Current records show that there are 1,004 species known which presents the researcher a wealth of chlorotoxins with which to analyze for effective treatments to disease states such as cancer, alzheimer's, epilepsy, inflammation and pain management. The non-disulfide-bridged scorpion venom peptide has become a crucial substance to initiate pharmacologic activities including antibacterial, antifungal, antimalarial, antiviral and anticancer activities [62, 63]. Effects of Animal Venoms and Toxins on Hallmarks of Cancer Janeyuth Chaisakul1, Wayne C. Hodgson2, Sandjaya Kuruppu2,3, Naiyarat Prasongsook4 1. Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok 10400, Thailand, 2. Monash Venom Group, Department of Pharmacology, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800. Australia, 3. Department of Biochemistry & Molecular Biology, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia, 4. Division of Medical Oncology, Department of Medicine, Phramongkutklao Hospital, Bangkok 10400, Thailand, Chaisakul J, Hodgson W C, Kuruppu S, Prasongsook N. Effects of Animal Venoms and Toxins on Hallmarks of Cancer. J. Cancer 2016; 7(11):1571-1578. doi:10.7150/jca.15309. Available from http://www.jcancer.org/v07p1571.htm. These references are hereby incorporated by reference herein for all purposes.
Scorpion Venoms
Chlorotoxin, a 36-amino acid basic peptide from the venom of the scorpion, binds in vitro to medulloblastomas, neuroblastomas, ganglioneuromas, melanomas, pheochromocytomas and small cell lung carcinomas and to mice gliomas. Chlorotoxins have also been effective in targeted radiotherapy of gliomas in mice. Scorpion venom containing chlorotoxins have been used to treat specific cancer tumors.
An example is that Bengalin chlorotoxin, isolated from the Indian black scorpion (Heterometrus Bengalis Koch), a large protein chlorotoxin, induces apoptosis in human leukemic cells in vitro. Bengalin also shows efficacy in a rat model of osteoporosis, but exhibits subacute cardiotoxicity. Toxicon. 2010 February-March, 55(2-3):455-61. doi: 10.1016/j.toxicon.2009.09.013. Epub 2009 Oct. 2. https://www.ncbi.nlm.nih.gov/pubmed/19800909 Chloride Movements Across Cellular Membranes Zhiwei Cai, . . . David N. Sheppard, in Advances in Molecular and Cell Biology, 2006.
Nature has blessed investigators of cation channels with an armamentarium of peptide toxins to selectively eliminate different types of cation currents. Disappointingly, similar tools have, for a long time, been unavailable to investigators of anion channels. DeBin et al. (1993) purified a 4.1 kDa basic peptide from scorpion venom with sequence similarity to small insectotoxins. Because this peptide inhibited outwardly rectifying Cl− channels reconstituted into planar lipid bilayers, DeBin et at (1993) named this toxin chlorotoxin. Subsequently, Maertens et al. (2000) demonstrated that sub-micromolar concentrations of chlorotoxin were without effect on volume-regulated, Ca2+-activated, and CFTR Cl− channels. Based on their data Maertens et al. (2000) concluded that chlorotoxin is not a general Cl− channel inhibitor.
Peptide toxins have been valuable probes in efforts to identify amino acid residues that line the permeation pathway of cation-selective channels. McCarty et al, in Am J Physiol Cell Physiol. 2004 November; 287(5):C1328-41. Epub 2004 Jul. 7, entitled, Inhibition of CFTR channels by a peptide toxin of scorpion venom. Fuller M D1, Zhang Z R, Cui G, Kubanek J, McCarty N A. searched for peptide toxins that inhibit the CFTR Cl− channel with the aim of identifying new tools to probe CFTR structure and function. In their initial study, Fuller et al. (2004) demonstrated that scorpion venom contains a low-molecular-weight peptide toxin that reversibly inhibits recombinant human CFTR expressed in Xenopus oocytes only when applied to the intracellular side of the membrane. Subsequently, Fuller et al. (2005) demonstrated that the peptide toxin preferentially inhibits CFTR when the channel is closed, suggesting that the toxin is a state-dependent blocker of the CFTR Cl− channel. Of note, the off-rate for the interaction of the toxin with CFTR is one hundred times slower than that of glibenclamide (Fuller et al. 2005). This argues well for the purification of a high-affinity peptide blocker of the CFTR Cl− channel.
Looking at Animal Toxins in Biotechnological Applications, as referenced in Animal Toxins, Jean-Marc Sabatier, Michel De Waard, in Handbook of Biologically Active Peptides (Second Edition), 2013, the group of Wonnacott showed that the subcellular distribution of alpha7 nicotinic acetylcholine receptors can be investigated by coupling alpha bungarotoxin to gold nanoparticles. In that respect, toxins seem perfect tools to target anticancer agents directly to the site of tumor in vivo if their targets are overexpressed in tumors. For instance, the G protein-coupled receptors (BBR1, BBR2, and BBR3) of bombesin, a 14 amino acid peptide from frog skin (specifically, the European fire-bellied toad Bombina bombina), are overexpressed in small cell carcinoma of lung, gastric cancer, neuroblastoma 21 and human prostate cancer. This property has been used to prepare bombesin derivatives harboring lutetium-1777 for prostate cancer targeting, in vivo imaging, and therapeutic intervention.24 Another successful example for tumor applications includes chlorotoxin,16,29 a 36-mer peptide with four (4) disulfide bridges initially isolated from the venom of the Israeli scorpion Leiurus quinquestriatus. Although initially developed for the diagnosis and treatment of glioma, chlorotoxin specifically labels cancer cells from other solid tumors, as well as melanoma, small cell lung carcinoma, neuroblastoma, medulloblastoma, Ewing's sarcoma, and pheochromacytoma. The identity of the biomarker on which it binds is still under debate (initially a chloride channel, then matrix metalloprotein 2, and now, which seems more probable, annexin 2A). Currently, a 131 iodinated version of the toxin from Eisai (TM601) has successfully ended conical research phase II for the treatment of recurrent glioma and has obtained FDA approval to go to phase III clinical trials. Besides, it has also obtained FDA approval to investigate the effect of TM601 on newly occurring glioma. TM601 is extremely stable, presents no immunogenicity and produces no toxicity in humans. Several derivative molecules (termed TM602, TM604, etc.) have been produced to facilitate phenotyping and histological staining, and patient treatment. The door is now open for use of other toxins in cancer diagnosis and treatment, BmKCT, which presents 68% amino acid sequence identity with chlorotoxin, also targets glioma in vivo and prevent its progression. Similarly, the nontoxic B subunit of the pathogen-produced Shiga toxin known to bind to the glycosphingolipid Gb3 which is overexpressed in some tumors specifically labels human colorectal carcinoma in nude mice.33 Other technological applications are possible with toxins. The 12 amino acid peptide Tet1, derived from tetanus toxin is an efficient vector for the delivery of plasmid DNA in complex to polyethylenimine (22 kDa). A similar fragment of tetanus toxin, when placed in fusion to the reporter protein GFP, allows mapping of synaptic connections of the mammalian central nervous system.
Most animal toxins hit cell surface receptors. This is by far the most straightforward means to interfere with signaling pathways for peptides as these molecular entities are sometimes considered unable to cross the cell plasma membrane. There are many exceptions to this belief, as some animal toxins target intracellular ion channel receptors. This occurs with toxins targeting the ryanodine receptor, an intracellular calcium channel located in the membrane of the endoplasmic reticulum and controls cytosolic Ca2+ release. These toxins present intriguing peptide sequences that efficiently favor their entry into the cytoplasm. Ion channel recognition and cell permeation can easily be dissociated to retain the latter property. Also, cell penetration can be derived for the cell entry of other compounds of pharmaceutical or imaging interests. Nanoparticles potential: types, mechanisms of action, actual in vitro and animal studies, recent patents, Gerardo Caruso, Maria Caffo, in Innovative Brain Tumor Therapy, 2014 4.3.3.
An estimated 40% of clinically approved drugs fall into the category where either the natural compound itself or a modified version is the approved drug. These include statins (found in bacterial secretions) used to lower cholesterol, quinines (found in cinchona trees) as anti-malaria, and paclitaxel (found in yew trees) as anti-cancer medication.
Many of these natural products are toxins produced by plants or animals as a form of defense. And scorpion venom has been gaining interest as a source of new drugs. It contains a mixture of biological chemicals called peptides, some of which are known to trigger cell death by forming pores in biological membranes. Cell death can be useful if we are able to target, say, tumor cells to auto-destruct.
Researchers investigating the use of scorpion venom as a cancer treatment have identified certain chemicals called peptides, contained in the venom, that can help destroy cancer cells and avoid the side effects of chemotherapy and other conventional cancer treatments. The peptide, chlorotoxin, is the same chemical that paralyzes a scorpion's prey. In one study, published in 2015 by Science Daily, researchers found that these peptides bind specifically to cancer cells and shrink and destroy them.
These toxins can have very potent effects. For instance, one particular small peptide, known as TsAP-1, isolated from the Brazilian yellow scorpion (Tityus serrulatus), has both, anti-microbial and anti-cancer properties. http://www.iflscience.com/health-and-medicine/how-scorpion-venom-could-yield-new-cancer-treatment/.
Additionally, as sited in smithsonian.com, Scorpion Venom is helping treat cancer patients. A potential source of effective chlorotoxins is the venom from Scorpions that are part of the order Scorpiones and the class Arachnida. They are invertebrates that possess eight legs and a two-segmented body composed of a cephalothorax and abdomen. This is the classification of scorpions: Kingdom Animalia (Animals); Phylum: Arthropoda (Arthropods); Subphylum: Chelicerata; Class: Arachnids (Arachnids); and Order: Scorpiones (Scorpions). Current records show that there are 1,004 known species. The number of species and the potential of compounds from the more than 1000 known species combined with the knowledge base of both native American Indian homeopathic medicine and other homeopathic literature indicate that there is a wealth of opportunity in the chlorotox's of scorpion species to elevate the symptoms of effective treatments to disease states such as heart disease, cancer, alzheimer's, epilepsy, inflammation and pain management.
The largest of the scorpion families is the Buthidae with over 800 scorpion species. They live mostly in tropical, subtropical, and partly in temperate habitats, except New Zealand and Antarctica.
Seventy-two scorpion species, belonging to Hemiscorpiidae, are known to inhabit all continents, particularly in tropical and subtropical habitats, with the exception of North America. With respect to the invention and the disclosure of scorpions the following Scorpion family's are include by definition: Bothriuridae, Buthidae, Caraboctonidae, Chactidae, Chaerilidae Diplocentridae, Euscorpiidae, Gigantoscorpionidae, Hemiscorpiidae, Palaeopisthacanthidae, Pseudochactidae, Scorpionidae, Superstitioniidae, Typhlochactidae and Vaejovidae.
Some of the world's largest scorpions belong to Scorpionidae family, which has approximately 240 scorpion species. Included in this family is the emperor scorpion (Pandinus imperator), one of the largest scorpion species known. Another giant is the Heterometrus swammerdami, which can reach lengths of twenty (20) centimeters.
The large number of venom producing scorpions makes for promising possibilities to find a significant number of pharmaceutical active molecules, because all true scorpion species have venom to kill or paralyze prey. Effects of a scorpion sting vary for humans, since some experience nothing more than a kind of numbness due to the sting, while sensitive individuals can die from the poisonous venom.
For example, in the venom of the Centruroides tecomanusscorpion from Colima, a southwest state of Mexico, over a hundred proteins have been found and identified as possessing “possible” toxic effect against cancer cells according to a scientific study. In preliminary investigations, researchers have identified peptides (amino acid molecules) that destroy cancer cells in vitro by binding to cancer cells and causing death of the cancer cell.
Research to date shows that natural based formulations especially designed from natural phytonutrients and natural chlorotoxins can be used for targeting cancer, heart disease, alzheimer's, epilepsy, inflammation and pain management.
Hence, there is need for a formulation comprised of promising natural based formulations, especially phytonutrients and natural chlorotoxins, for targeting cancer and with less or no side effects. Also, there is a need for a method for synthesizing the formulation comprising phytonutrients and natural chlorotoxins for cancer indications.
Hence, there is a needed for a formulation comprised of natural based formulations, especially phytonutrients and natural chlorotoxins for targeting cancer, heart disease, alzheimer's, epilepsy.
Also there is a needed for a formulation comprised of promising natural based formulations, especially phytonutrients and natural chlorotoxins, for targeting inflammation and pain management.